Abstract
Mechanical ventilation (MV) can save the lives of patients with sepsis. However, MV in both animal and human studies has resulted in ventilator‐induced diaphragm dysfunction (VIDD). Sepsis may promote skeletal muscle atrophy in critically ill patients. Elevated high‐mobility group box‐1 (HMGB1) levels are associated with patients requiring long‐term MV. Ethyl pyruvate (EP) has been demonstrated to lengthen survival in patients with severe sepsis. We hypothesized that the administration of HMGB1 inhibitor EP or anti‐HMGB1 antibody could attenuate sepsis‐exacerbated VIDD by repressing HMGB1 signalling. Male C57BL/6 mice with or without endotoxaemia were exposed to MV (10 mL/kg) for 8 hours after administrating either 100 mg/kg of EP or 100 mg/kg of anti‐HMGB1 antibody. Mice exposed to MV with endotoxaemia experienced augmented VIDD, as indicated by elevated proteolytic, apoptotic and autophagic parameters. Additionally, disarrayed myofibrils and disrupted mitochondrial ultrastructures, as well as increased HMGB1 mRNA and protein expression, and plasminogen activator inhibitor‐1 protein, oxidative stress, autophagosomes and myonuclear apoptosis were also observed. However, MV suppressed mitochondrial cytochrome C and diaphragm contractility in mice with endotoxaemia (P < 0.05). These deleterious effects were alleviated by pharmacologic inhibition with EP or anti‐HMGB1 antibody (P < 0.05). Our data suggest that EP attenuates endotoxin‐enhanced VIDD by inhibiting HMGB1 signalling pathway.
Highlights
Myonuclear apoptosis can be accelerated by mitochondrial reactive oxygen species (ROS), elevated cellular calcium lev‐ els and sarcoplasmic reticulum stress‐induced activation of calpain and caspase‐3.20,24 sepsis and Mechanical ventilation (MV)‐induced oxidative stress may up‐regulate the production of inflammatory mediators, including high‐mobility group box 1 (HMGB1), interleukin 6 (IL‐6) and plasminogen activator inhibitor‐1 (PAI‐1),[9,15,25,26,27,28,29] and subse‐ quently impair diaphragm activities
We hypothesized that the administration of ethyl pyruvate or anti‐HMGB1 antibody would diminish HMGB1 expres‐ sion, diaphragmatic structural damage, generation of free radicals, proteolytic protein synthesis and mitochondrial dysfunction and re‐ store muscle contractility in the diaphragm of mice with or without endotoxaemia exposed to MV
Diaphragm dysfunction is a critical determinant that negatively influences the clinical outcome of critically ill patients and typically accompanies prolonged MV exposure, and increases ventilator‐associated com‐ plications, and mortality.[1]
Summary
Mechanical ventilation (MV) is a life‐saving treatment for patients suffering from acute respiratory failure, but it may lead to pa‐ tient's reliance on ventilators because of a resultant and rapid decline of diaphragm muscle endurance and strength, which is termed ven‐ tilator‐induced diaphragmatic dysfunction (VIDD).[1,2,3] Numerous studies have determined that VIDD could raise weaning failure rate, intensive care unit (ICU) stay and medical expenditures.[2,3] the mechanisms of VIDD, presumably encompassing a multistep. We hypothesized that the administration of ethyl pyruvate or anti‐HMGB1 antibody would diminish HMGB1 expres‐ sion, diaphragmatic structural damage, generation of free radicals, proteolytic protein synthesis and mitochondrial dysfunction and re‐ store muscle contractility in the diaphragm of mice with or without endotoxaemia exposed to MV
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